| Reference : The role of neuromelanin in dopaminergic neuron demise and inflammation in idiopathic... |
| Dissertations and theses : Doctoral thesis | |||
| Life sciences : Biochemistry, biophysics & molecular biology | |||
| Systems Biomedicine | |||
| http://hdl.handle.net/10993/52611 | |||
| The role of neuromelanin in dopaminergic neuron demise and inflammation in idiopathic Parkinson's disease | |
| English | |
Smajic, Semra  [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology > ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology] | |
| 28-Sep-2022 | |
| University of Luxembourg, Esch-sur-Alzette, Luxembourg | |
| Docteur en Biologie | |
| 338 | |
| Grünewald, Anne | |
| Schwamborn, Jens Christian | |
| [en] Parkinson's disease ; Neuroinflammation ; Neuromelanin | |
| [en] For a very long time, the main focus in Parkinson’s disease (PD) research was the
loss of neuromelanin-containing dopaminergic neurons from the substantia nigra (SN) of the midbrain - the key pathological feature of the disease. However, the association of neuronal vulnerability and neuromelanin presence has not been a common study subject. Recently, cells other than neurons also gained attention as mediators of PD pathogenesis. There are indications that glial cells undergo disease-related changes, however, the exact mechanisms remain unknown. In this thesis, I aimed to explore the contribution of every cell type of the midbrain to PD using single-nuclei RNA sequencing. Additionally, the goal was to explore their association to PD risk gene variants. As we identified microgliosis as a major mechanism in PD, we further extended our research to microglia. We sought to investigate the relation of microglia and neuromelanin. Thus, we aimed to, by means of immunohistochemical staining, imaging and laser-capture microdissection-based transcriptomics, elucidate this association on a single-cell level. This work resulted in the first midbrain single-cell atlas from idiopathic PD subjects and age- and sex-matched controls. We revealed SN-specific microgliosis with GPNMB upregulation, which also seemed to be specific to the idiopathic form of the disease. We further observed an accumulation of (extraneuronal) neuromelanin particles in Parkinson’s midbrain parenchyma, indicative of incomplete degradation. Moreover, we showed that GPNMB can be alleviated in microglia in contact with neuromelanin. Taken together, we provide evidence of a GPNMB-related microglial state as a disease mechanism specific to idiopathic PD, and highlight neuromelanin as an important player in microglia disease pathology. Further investigations are needed to understand whether the modulation of neuromelanin levels could be relevant in the context of PD therapy. | |
| Fonds National de la Recherche - FnR | |
| http://hdl.handle.net/10993/52611 | |
| FnR ; FNR12244779 > Jens Schwamborn > PARK-QC > Molecular, Organellar And Cellular Quality Control In Parkinson’S Disease And Other Neurodegenerative Diseases > 01/05/2018 > 31/10/2024 > 2017 |
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